ROLE OF MDM2, P300, P19ARF IN P53 UBIQUITINATION

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DESCRIPTION (Applicant's Description): Candidate: Steve Grossman's career goal is to become an independent cancer researcher focused on the mechanisms of tumorigenesis surrounding p53 and its biochemical regulation by MDM2, p300/CBP and pl9ARF. In the long term, ideas generated from basic research in tumor mechanisms would be applied specifically to the field of GI malignancy, where he is already a practicing clinician. For the short term, the Howard Temin Award will assist his transition to full independence as a cancer research scientist at Dana-Farber Cancer Institute, where he was most recently promoted to Assistant Professor (Developing). The next year to two years will be critical for polishing his research skills under the mentorship of Dr. David Livingston, and establishing a presence in the field of p53 biology, thus allowing for a smooth transition to independence. Environment: The Dana-Farber Cancer Institute and nearby Harvard Medical School, provides an excellent collaborative environment for the completion of the research goals outlined in this proposal-- both during the mentored and unmentored phases of the grant. Dr Livingston is generally regarded as an excellent scientific mentor, and there is a supportive and stimulating intellectual and scientific environment maintained in his laboratory. Research: The specific research aims are: 1. to purify to homogeneity the ubiquitin ligase complex responsible for p53 ubiquitination, and determine if MDM2 and p300/CBP function within this complex. 2. to identify MDM2 post- translational modifications and determine their effect on the ability of MDM2 to ubiquitinate and direct the degradation of p53. 3. to analyze the mechanism by which pl9ARF can regulate the MDM2-driven ubiquitination and degradation of p53, and identify any possible role for p300/CBP in pl9ARF action. 4. to identify novel targets of both MDM2 and pl9ARF for ubiquitination and/or degradation, and the physiologic role for MDM2/pl9ARF regulation of these targets.